Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events
© 2023 by The American Society of Hematology..
In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 μg/mL. However, a higher Ctrough_1 (≥39 μg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 μg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 μg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131.
| Errataetall: |
CommentIn: Blood. 2023 Aug 24;142(8):680-682. - PMID 37616024 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:142 |
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| Enthalten in: |
Blood - 142(2023), 8 vom: 24. Aug., Seite 700-710 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Takahashi, Takuto [VerfasserIn] |
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| Links: |
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| Themen: |
7D0YB67S97 |
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| Anmerkungen: |
Date Completed 25.08.2023 Date Revised 24.03.2024 published: Print ClinicalTrials.gov: NCT01743131 CommentIn: Blood. 2023 Aug 24;142(8):680-682. - PMID 37616024 Citation Status MEDLINE |
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| doi: |
10.1182/blood.2023020035 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 μg/mL. However, a higher Ctrough_1 (≥39 μg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 μg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 μg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131 | ||
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| 700 | 1 | |a Betz, Kayla |e verfasserin |4 aut | |
| 700 | 1 | |a Suessmuth, Yvonne |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Alison |e verfasserin |4 aut | |
| 700 | 1 | |a Neuberg, Donna S |e verfasserin |4 aut | |
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| 700 | 1 | |a Lalefar, Nahal |e verfasserin |4 aut | |
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| 700 | 1 | |a Pulsipher, Michael A |e verfasserin |4 aut | |
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